Background: To investigate the mediation effects of physical activity (PA) on the relationship between the perceived neighborhood aesthetic environment and overweight/obesity in free-living South Africans. Methods: A cross-sectional study of 671 adults aged ≥ 35 years was analyzed. PA was assessed using the validated International Physical Activity Questionnaire. Perceived neighborhood aesthetics was assessed using the Neighborhood Environment Walkability Scale Questionnaire. Results: Of 671 participants, 76.0% were women, 34.1% aged 45–54 years, and 69.2% were overweight or obese. In adjusted logistic regression models, overweight/obesity was significantly associated with neighborhood aesthetics [odds ratio (OR) = 0.68; 95% confidence interval (CI), 0.50–0.93] and PA (OR = 0.65; 95% CI, 0.65–0.90). In expanded multivariable models, overweight/obesity was associated with age 45–55 years (OR = 1.59; 95% CI, 1.05–2.40), female gender (OR = 6.24; 95% CI, 3.95–9.86), tertiary education (OR = 4.05; 95% CI, 1.19–13.86), and urban residence (OR = 2.46; 95% CI, 1.66–3.65). Conclusion: Aesthetics was positively associated with PA; both aesthetics and PA were negatively associated with overweight and obesity. There was no evidence to support a significant mediating effect of PA on the relationship between aesthetics and overweight/obesity. Future studies should consider objective assessment of aesthetics and PA. In addition, future studies should consider using longitudinal design to evaluate food-related environments, which are related to overweight or obesity.